- Email: [email protected]
Combined concomitant boost radiotherapy and chemotherapy in stage III–IV head and neck carcinomas: A comparison of toxicity and treatment results with those observed after radiotherapy alone
Annals of Oncology 8: 681-684,1997. © 1997 Kluwer Academic Publishers Primed in the Netherlands.
Original article Combined concomitant boost radiotherapy and chemotherapy in stage III-IV head and neck carcinomas: A comparison of toxicity and treatment results with those observed after radiotherapy alone A. S. Allal,1 S. Bieri,1 R. Miralbell,1 P. Dulguerov,2 A: Bardina,1 W. Lehmann2 & J. M. Kurtz1 Divisions of 'Radiation Oncology and 2Head and Neck Surgery, University Hospital, Geneva, Switzerland
up for the surviving patients was 21 and 31 months for the RT and RT-CT groups respectively. Background: Alteration of radiation therapy (RT) fractionaResults: Grade 3-4 acute toxicity (RTOG) was observed in tion and the combination of chemotherapy (CT) with RT 73% and 86% of patients, and grade 3 dysphagia in 31% and represent two predominant fields of current research in the 57% (P = 0.02) respectively in the RTand RT-CT groups. The treatment of head and neck carcinomas. To assess the potential rates of grade 3—4 late complications were similar in the two integration of these twofields,a retrospective comparison of groups (5% vs. 12%). At three years, actuarial loco-regional toxicity and treatment outcome was carried out in stage III-IV control (LRC) was 57% and 66% (P = 0.66) and overall survival patients treated with a concomitant boost RT schedule with or was 56% and 47% (P = 0.99) in the RT and RT-CT groups without CT. respectively. Patients and methods: Fifty-two patients were treated by RT Conclusions: While acute toxicity was higher compared alone and 35 by RT and CT. In the RT group, there were with RT alone, this accelerated RT schedule was feasible in significantly fewer T3-4 tumors (56% vs. 88%, P - 0.002) and association with 5-FU/CDDP, even administered concomihigher proportion of planned neck dissections (35% vs. 14%, tantly. Despite the significant proportion of more advanced P = 0.047). The planned total dose was 69.9 Gy delivered over disease in the RT-CT group, LRC was similar to that obtained 5.5 weeks. In 10 cases CT was given before RT and in 25 by RT alone. Combinations of concomitant boost RT and concomitantly with RT, either alone or with neoadjuvant and/ chemotherapy merit further investigation in prospective trials. or adjuvant CT. All patients but two had cisplatin-based (CDDP, 100 mg/m2) CT, associated in 28 patients with Key words: accelerated radiotherapy, chemotherapy, head and 5-fluorouracil (5-FU, 1000 mg/m2/24 h x 5). The median follow- neck cancer Summary
The prognosis of patients with advanced head and neck carcinomas treated by standard radiation therapy (RT) is generally very unfavorable [1-3]. Both the use of unconventional fractionation schedules and the adjunction of chemotherapy to RT are undergoing investigation in the hope of improving these unsatisfactory results [417]. The encouraging initial results of the concomitant boost technique [9, 18] led in 1991 to the introduction at the University Hospital of Geneva of a modified concomitant boost schedule in which the boost to the clinically involved sites was delivered in a progressively accelerated fashion during the last 3.5 weeks of a 5.5 week treatment course. For stage III-IV disease, chemotherapy was initially added sequentially prior to RT and then progressively more frequently in a concomitant fashion. In order to establish whether or not a concomitant boost schedule is compatible with the simultaneous administration of chemotherapy, the therapeutic outcome and toxicity of the combined treatment have been retrospectively analyzed and compared with those
obtained in a group of patients treated during the same period with the identical RT regimen but without chemotherapy.
Patients and methods Patients From January 1991 to October 1995, 87 patients with resectable or unresectable stage III-IV head and neck carcinomas were treated with concomitant boost RT, of whom 35 (40%) received combined chemoradiotherapy. Compared with patients treated with radiotherapy alone (RT group), those receiving chemotherapy (RT-CT group) tended to have bulkier disease. The characteristics of the two groups of patients are given in Table 1.
Radiation therapy The treatment schedule planned to deliver a total dose of 69.9 Gy in 41 fractions over a period of 38 days. The basic course, including all involved sites and areas of potential microscopic disease (generally the primary tumor area and both sides of the neck down to the clavicles), was given in daily fractions of 1.8 Gy, five times a week to a total dose
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
Introduction
682 Table 2. Acute morbidities in the two groups of patients.
Table 1. Patient characteristics.
Mean age (standard deviations) Gender: male/female WHO performance status 0-1 2-3 Tumor location Oral cavity + oropharynx Hypopharynx + larynx Nasopharynx TN stage Tl-2
RT-CT group (35 patients)
61 years (11) 39/13
54 years (16) 24/11
0.04
36(72%) 14(28%)
31(89%) 4(11%)
0.1
27(52%) 19(36%) 6(12%)
21(60%) 9(26%) 5(14%)
23(44%) 29(56%) 11(21%) 41(79%)
4(12%) 31(88%) 8(23%) 27(77%)
0.002
18(35%) 34 (65%)
7(20%) 28 (80%)
0.15
Overall grade 3-4 Grade 3—4 mucositis Grade 3 dysphagia Hospitalisation Median duration (range) Nasogastric tube or gastronomy Median duration (range) Median weight loss during radiotherapy (range)
RT group (52 patients)
RT-CT group (35 patients)
38 (73%) 34 (65%) 16(31%) 9(17%) 12 days (4-150)
30 (86%) 24 (69%) 20 (57%) 14(40%) 19 days (11-150)
13(25%) 38 days (4-150)
18(51%) 38 days (11-150)
4.6 kg (0-14)
0.2 1
0.02 0.02
0.02
4 kg (0-11)
continuous 24-hour intravenous infusion of 5-FU (1000 mg/m ) for five days. During RT, the dose of 5-FU was reduced by 20%-40% in the second course, according to the severity of the acute mucosal reactions. Statistical methods
of 50.4 Gy over 5.5 weeks. The boost to initial sites of macroscopic tumor mvolvement consisted of 13 fractions of 1.5 Gy (19.5 Gy) and was given as a second daily fraction, starting the last day of the second week of the basic treatment, in a progressively accelerated fashion (Figure 1). The minimum interval between the two daily fractions was six hours. The larger volume was treated generally with two opposed laterals and one anterior field, using 6 MV photon beams in most patients. The field arrangement for the boost was individualized according to the tumor extent and location. The cervical spinal cord was blocked at a dose of 45 Gy or less, and irradiation of the posterior neck was then continued with electrons of appropriate energy. The supraclavicular lymph nodes generally received a dose of 45-50.4 Gy in 25-28 fractions. No specific technical modifications were used in the group of patients receiving chemotherapy. Surgery No patient received surgery to the primary tumor. Before RT, a uni- or bilateral neck dissection was performed in 18 patients in the RT group and five in the RT-CT group (/> = 0.047), and two patients in the RT group had an adenectomy. Otherwise surgery was reserved for salvage of loco-regional failures.
The actuarial overall and disease-free survival rates as well as actuarial local and loco-regional control rates were calculated by using the Kaplan-Meier method [19]. The Fisher's exact test, the unpaired ttest, and the logrank test were used to assess for significant differences between simple proportions, means, and survival curves respectively.
Results All the patients completed the planned irradiation schedule except one in the RT-CT group. All three treatment interruptions due to acute toxicity occurred in the RT-CT group (split duration 5, 17, and 35 days). The median overall treatment time was 41 days (range 36-50 days) for the RT group and 39 days (range 37-79) for the RT-CT group. The median tumor dose for both groups was similar (69.9 Gy, range 62.5-72.9). Morbidity
According to the RTOG grading system [20], all acute reactions were grade 2 or more. The majority were grade Chemotherapy 3 reactions, with only one patient in the RT group and two patients in the RT-CT group presenting with grade 4 In the initial patients chemotherapy was delivered sequentially prior to acute toxicity. The main acute toxicity parameters for starting RT. Apparently satisfactory tolerance led to a gradual shift toward the administration of an increasing proportion of the chemo- the two groups are displayed in Table 2. In the RT-CT therapy concomitantly with RT. Thus in 10 cases chemotherapy was group, grade 3 dysphagia was more frequent with conadministered only prior to, and in 25 concomitantly with RT, either comitant (64%) than with neoadjuvant (45%) chemoalone or with neoadjuvant and/or adjuvant chemotherapy. therapy administration. Except for two patients treated with weekly carboplatin, all patients According to the World Health Organization (WHO) received cisplatin (CDDP), associated with 5-fluorouracil (5-FU) in 28 grading system [21], 12 patients (36%) in the RT-CT patients, with epirubicin + bleomycin in four patients, and administered alone in one patient. Twenty-two (63%) patients received three group presented with grade 3-4 hematological complicycles, nine (26%) two cycles, and two (6%) one cycle. In patients cations. Grade 3 gastrointestinal complications were obreceiving at least part of their chemotherapy concomitantly with RT, served in four patients, and grade 3 skin reactions in one chemotherapy consisted of CDDP and 5-FU in 21 patients (84%). Fourteen patients received one cycle, and seven patients two cycles, patient. Three patients presented with a vascular thromadministered generally on the first and the fourth week of RT. CDDP bosis requiring anticoagulation, three with alopecia and (100 mg/m ) was given as a rapid intravenous infusion followed by one with hearing impairment.
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
NO Nl-3 AJCC stage III IV
RT group (52 patients)
683 Week
1
2
3
4
5
6
Wide fields (50.4 Gy/28 fr.)
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXX
X
X_X_X
x_xxx
XXX
Boost (19.5Gy/13 fr.)
X
Figure 1. Schematic representation of the radiotherapy protocol.
Clinical outcome
At last follow-up, 31 patients in the RT group and 17 in the RT-CT group were still alive, and one patient in each group was lost to follow-up (14 and 11 months). In patients having died, head and neck cancer was considered the cause of death in 14 of 20 patients in the RT group and 11 of 17 patients in the RT-CT group. The median follow-up for the surviving patients was 21 months (range 2-60) and 31 months (range 4-54) for the RT and RT-CT groups, respectively. Local and locoregional control rates were estimated for patients with a minimum follow-up of one year and without taking into account the contribution of salvage surgery. At three years actuarial local control was 70% in the two groups and actuarial loco-regional control was 57% and 66% for the RT and RT-CT groups, As expected from any accelerated RT program, the rate respectively (P = 0.66). The three-year actuarial overall of grade 3-4 acute reactions was high and was increased survival was 56% and 47% (P = 0.99), and the three-year by the adjunction of chemotherapy (Table 2). Indeed, disease-free survival was 53% and 60% for the RT and compared with the RT group, there was greater overall the RT-CT groups, respectively (P - 0.8). acute toxicity and significantly more grade 3 dysphagia in the RT-CT group, and patients receiving combined treatment more frequently required hospitalization and needed significantly more nutritional support. However, Discussion it is the authors' impression that acute toxicities were Unconventional radiation fractionation schedules and equally manageable in the two groups, particularly when the association of chemotherapy with RT represent the timely supportive care was provided. The most signifimain innovative approaches currently under study for cant therapeutic disadvantage of combined treatment the treatment of unfavorable head and neck cancers. was the occasional disruption of RT delivery. In this retrospective analysis, locoregional control, Progress in this area has been impeded by the problem of unacceptable acute toxicity, and various strategies disease-free survival, and overall survival were not sighave been developed to assure the feasibility of these nificantly different between the two groups. This appears aggressive treatment programs. In the case of acceler- to be in contradiction to the results of some randomized ated RT schedules, tolerance has been variously im- studies comparing concomitant chemoradiotherapy with proved by reducing the total dose (very accelerated RT alone, which demonstrate significantly better loco-
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
Three patients in the RT group and one in the RT-CT group died during the three months following radiotherapy of causes not clearly related to tumor progression. One patient, who refused supportive care, died of malnutrition; one malnourished patient died from Candida septicemia; one patient died from pneumonia as a consequence of severe laryngeal edema; and one patient died from a massive oropharyngeal hemorrhage in a setting of post-chemotherapy thrombopenia. Seventy-three patients were evaluable for long-term complications (patients with a minimum follow-up of three months and with available data). Most complications were RTOG grade 2 (52% and 42% in the RT and RT-CT groups, respectively). Grade 3-4 complications were observed in 5% and 12% in the RT and RT-CT groups, respectively (P = 0.4).
continuous course), interposing a treatment gap (accelerated split course), or reducing the volume submitted to accelerated fractionation (concomitant boost). On the other hand, for combinations of chemo- and radiotherapy, many investigators have preferred sequential or alternating schedules, in order to avoid the toxicity associated with the concomitant administration of the two modalities. Moreover, chemotherapy has often been limited to single agents, and RT administered using standard fractionation or using split course techniques. In contrast, the feasibility of concomitant chemotherapy and continuous accelerated RT has not been extensively investigated. There is increasing evidence that locoregional control can be improved through the use of various hyperfractionated and accelerated RT programs [1, 4, 6, 9, 22]. Considering the logistical convenience and the encouraging initial results of concomitant boost schedules [9], a modified concomitant boost program was developed, in which the 13 second daily fractions were given in a progressively accelerated manner starting on day 12 of the basic treatment. This schedule design was based on the notion, as suggested by both experimental and clinical data [23, 24], that cancer clonogen repopulation may become significant as early as two weeks after initiation of RT, and that the incremental dose required to compensate for tumor proliferation might increase progressively toward the end of treatment. At the same time, and with the aim of increasing the efficacy of this accelerated RT schedule, selected patients with very advanced disease were given chemotherapy. Initially chemotherapy was given sequentially before RT, but since this mode of administration had come under serious criticism [8, 11, 25], a decision was made to give at least part of the chemotherapy concomitantly with irradiation. The choice of 5-FU/CDDP was motivated by the reported activity of this combination in head and neck cancers [3, 12] and by the radiosensitizing properties attributed to CDDP [26, 27].
684
20.
References
21.
1. Horiot JC, Le Fur R, N'Guyen Tet al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992; 25: 231-41. 2. Sanchiz F, Milla A, Torner J et al. Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 1990; 19: 1347-50. 3. Merlano M, Vitale V, Rosso R et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992; 327: 1115-21. 4. Wang CC, Blitzer PH, Suit H. Twice-a-day radiation therapy for cancer of the head and neck. Cancer 1985; 55: 2100-4. 5. Van den Bogaert W, Van der Schueren E, Horiot JC et al. Early results of the EORTC randomized clinical trial on multiple fractions per day (MFD) and misonidazole in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1986; 12: 587-91. 6. Horiot JC, Bontemps P, Begg AC et al. Hyperfractionated and accelerated radiotherapy in head and neck cancers: Facts from trials, impact on standard practice. Eur J Cancer 1995; 31A (Suppl 5): S69. 7. Hong WK, Bromer R. Current concepts: Chemotherapy in head and neck cancer. N Engl J Med 1983; 308: 75-9. 8. Vokes EE, Weichselbaum RR, Lippman SM, Ki Hong W. Head and neck cancer. N Engl J Med 1993; 328: 184-94. 9. Ang KK, Peters LJ, Weber RS et al. Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 1990; 19: 1339^*5. 10. Wang CC. Carcinoma of the oropharynx. In Wang CC (eds): Radiation Therapy for Head and Neck Neoplasms. Chicago: Year Book Medical Publishers, 1990; 186-206. 11. Stell PM, Rawson NSB. Adjuvant chemotherapy in head and neck cancer. Br J Cancer 1990; 61: 779-87. 12. Taylor SG, Murthy AK, Caldarelli DD et al. Combined simulta-
22.
13.
14.
15.
16.
17.
18. 19.
23. 24.
25. 26. 27. 28. 29.
neous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer. J Clin Oncol 1989; 7: 846-56. Browman GP, Cripps C, Hodson DI et al. Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 1994; 12: 2648-53. Gupta NK, Pointon RC, Wilkinson PM. A randomised clinical trial to contrastradiotherapywith radiotherapy and methotrexate given synchronously in head and neck cancer. Clin Radiol 1987; 38: 575-S1. Fu KK, Phillips TL, Silverberg IJ et al. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: Update of a Northern California Oncology Group randomized trial. J Clin Oncol 1987; 5: 1410-8. Lo TCM, Wiley AL, Ansfield FJ et al. Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and orpharaynx: A randomized study. Am J Roentgenol RadiumTher Nucl Med 1976; 126: 229-35. Adelstein DJ, Saxton JP, Lavertu P et al. Concurrent radiation and chemotherapy versusradiotherapyalone in resectable stage III and IV squamous cell head and neck cancer. J Clin Oncol 1996; 15: 26 (Abstr). Knee R, Fields RS, Peters LJ. Concomitant boost radiotherapy for advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1985; 4: 1-7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. Perez CA, Brady LW. Overview. In Perez CA, Brady LW (eds): Principales and Practice of Radiation Oncology. Philadelphia: Lippincott, 1992; 51-5. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treament. Cancer 1981; 47: 207-14. Saunders MI, Disch S, Grosch, EJ et al. Experience with CHART. Int J Radiat Oncol Biol Phys 1991; 21: 871-S. Withers HR, Taylor JMG, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27: 131^46. Kummermehr J, Schropp K, Neuner M. Repopulation in squamous cell carcinoma AT 478 during daily irradiation. Experimentelle Tumor-therapie, Annual Report 1985, Munich, GSF-Bericht 31/85,1986; 31-6. Jacobs C. Adjuvant and neoadjuvant treatment of head and neck cancers. Semin Oncol 1991; 18: 504-14. Overgaard J, Khan AR. Selective enhancement of radiation response in C3H mammary carcinoma by cisplatin. Cancer Treat Rep 1981; 65: 501-3. Douple EB. Radiosensitization of hypoxic tumor cells by cis- and trans-dichiorodiammine platinum (II). Int J Radiat Oncol Biol Phys 1979; 5: 1369-72. Munro AJ. An overview of randomised controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995; 71: 83-91. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14: 838-47.
Received 31 January 1997; accepted 28 May 1997.
Correspondence to: A. S. Allal, MD Division of Radiation Oncology University Hospital 1211 Geneva 14 Switzerland
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
regional control [14—16], and suggest a statistically significant improvement in survival with combined treatment [28, 29]. However, as a result of patient selection, the composition of the two groups in the present study was not at all similar (Table 1). In particular, in the RTCT group there were fewer patients having had neck dissections and a higher percentage of T3-T4 tumors. It is thus impossible to draw conclusions from the current study regarding the potential benefits of the combined treatment. In the absence of randomized comparisons the choice of RT regimen for treating unfavorable head and neck cancers will be determined by convenience, toxicity profile, and the feasibility of administration simultaneously with effective antitumor agents. Although highly accelerated continuous regimens are likely to be incompatible with such combined therapy, our initial clinical results suggest that the concomitant boost program described in the present paper can be administered together with standard combination chemotherapy with acceptable toxicity. The locoregional control obtained in the present series of patients with stage III—IV disease is encouraging. A confirmation of these results in prospective studies appears justified.
Original article Combined concomitant boost radiotherapy and chemotherapy in stage III-IV head and neck carcinomas: A comparison of toxicity and treatment results with those observed after radiotherapy alone A. S. Allal,1 S. Bieri,1 R. Miralbell,1 P. Dulguerov,2 A: Bardina,1 W. Lehmann2 & J. M. Kurtz1 Divisions of 'Radiation Oncology and 2Head and Neck Surgery, University Hospital, Geneva, Switzerland
up for the surviving patients was 21 and 31 months for the RT and RT-CT groups respectively. Background: Alteration of radiation therapy (RT) fractionaResults: Grade 3-4 acute toxicity (RTOG) was observed in tion and the combination of chemotherapy (CT) with RT 73% and 86% of patients, and grade 3 dysphagia in 31% and represent two predominant fields of current research in the 57% (P = 0.02) respectively in the RTand RT-CT groups. The treatment of head and neck carcinomas. To assess the potential rates of grade 3—4 late complications were similar in the two integration of these twofields,a retrospective comparison of groups (5% vs. 12%). At three years, actuarial loco-regional toxicity and treatment outcome was carried out in stage III-IV control (LRC) was 57% and 66% (P = 0.66) and overall survival patients treated with a concomitant boost RT schedule with or was 56% and 47% (P = 0.99) in the RT and RT-CT groups without CT. respectively. Patients and methods: Fifty-two patients were treated by RT Conclusions: While acute toxicity was higher compared alone and 35 by RT and CT. In the RT group, there were with RT alone, this accelerated RT schedule was feasible in significantly fewer T3-4 tumors (56% vs. 88%, P - 0.002) and association with 5-FU/CDDP, even administered concomihigher proportion of planned neck dissections (35% vs. 14%, tantly. Despite the significant proportion of more advanced P = 0.047). The planned total dose was 69.9 Gy delivered over disease in the RT-CT group, LRC was similar to that obtained 5.5 weeks. In 10 cases CT was given before RT and in 25 by RT alone. Combinations of concomitant boost RT and concomitantly with RT, either alone or with neoadjuvant and/ chemotherapy merit further investigation in prospective trials. or adjuvant CT. All patients but two had cisplatin-based (CDDP, 100 mg/m2) CT, associated in 28 patients with Key words: accelerated radiotherapy, chemotherapy, head and 5-fluorouracil (5-FU, 1000 mg/m2/24 h x 5). The median follow- neck cancer Summary
The prognosis of patients with advanced head and neck carcinomas treated by standard radiation therapy (RT) is generally very unfavorable [1-3]. Both the use of unconventional fractionation schedules and the adjunction of chemotherapy to RT are undergoing investigation in the hope of improving these unsatisfactory results [417]. The encouraging initial results of the concomitant boost technique [9, 18] led in 1991 to the introduction at the University Hospital of Geneva of a modified concomitant boost schedule in which the boost to the clinically involved sites was delivered in a progressively accelerated fashion during the last 3.5 weeks of a 5.5 week treatment course. For stage III-IV disease, chemotherapy was initially added sequentially prior to RT and then progressively more frequently in a concomitant fashion. In order to establish whether or not a concomitant boost schedule is compatible with the simultaneous administration of chemotherapy, the therapeutic outcome and toxicity of the combined treatment have been retrospectively analyzed and compared with those
obtained in a group of patients treated during the same period with the identical RT regimen but without chemotherapy.
Patients and methods Patients From January 1991 to October 1995, 87 patients with resectable or unresectable stage III-IV head and neck carcinomas were treated with concomitant boost RT, of whom 35 (40%) received combined chemoradiotherapy. Compared with patients treated with radiotherapy alone (RT group), those receiving chemotherapy (RT-CT group) tended to have bulkier disease. The characteristics of the two groups of patients are given in Table 1.
Radiation therapy The treatment schedule planned to deliver a total dose of 69.9 Gy in 41 fractions over a period of 38 days. The basic course, including all involved sites and areas of potential microscopic disease (generally the primary tumor area and both sides of the neck down to the clavicles), was given in daily fractions of 1.8 Gy, five times a week to a total dose
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
Introduction
682 Table 2. Acute morbidities in the two groups of patients.
Table 1. Patient characteristics.
Mean age (standard deviations) Gender: male/female WHO performance status 0-1 2-3 Tumor location Oral cavity + oropharynx Hypopharynx + larynx Nasopharynx TN stage Tl-2
RT-CT group (35 patients)
61 years (11) 39/13
54 years (16) 24/11
0.04
36(72%) 14(28%)
31(89%) 4(11%)
0.1
27(52%) 19(36%) 6(12%)
21(60%) 9(26%) 5(14%)
23(44%) 29(56%) 11(21%) 41(79%)
4(12%) 31(88%) 8(23%) 27(77%)
0.002
18(35%) 34 (65%)
7(20%) 28 (80%)
0.15
Overall grade 3-4 Grade 3—4 mucositis Grade 3 dysphagia Hospitalisation Median duration (range) Nasogastric tube or gastronomy Median duration (range) Median weight loss during radiotherapy (range)
RT group (52 patients)
RT-CT group (35 patients)
38 (73%) 34 (65%) 16(31%) 9(17%) 12 days (4-150)
30 (86%) 24 (69%) 20 (57%) 14(40%) 19 days (11-150)
13(25%) 38 days (4-150)
18(51%) 38 days (11-150)
4.6 kg (0-14)
0.2 1
0.02 0.02
0.02
4 kg (0-11)
continuous 24-hour intravenous infusion of 5-FU (1000 mg/m ) for five days. During RT, the dose of 5-FU was reduced by 20%-40% in the second course, according to the severity of the acute mucosal reactions. Statistical methods
of 50.4 Gy over 5.5 weeks. The boost to initial sites of macroscopic tumor mvolvement consisted of 13 fractions of 1.5 Gy (19.5 Gy) and was given as a second daily fraction, starting the last day of the second week of the basic treatment, in a progressively accelerated fashion (Figure 1). The minimum interval between the two daily fractions was six hours. The larger volume was treated generally with two opposed laterals and one anterior field, using 6 MV photon beams in most patients. The field arrangement for the boost was individualized according to the tumor extent and location. The cervical spinal cord was blocked at a dose of 45 Gy or less, and irradiation of the posterior neck was then continued with electrons of appropriate energy. The supraclavicular lymph nodes generally received a dose of 45-50.4 Gy in 25-28 fractions. No specific technical modifications were used in the group of patients receiving chemotherapy. Surgery No patient received surgery to the primary tumor. Before RT, a uni- or bilateral neck dissection was performed in 18 patients in the RT group and five in the RT-CT group (/> = 0.047), and two patients in the RT group had an adenectomy. Otherwise surgery was reserved for salvage of loco-regional failures.
The actuarial overall and disease-free survival rates as well as actuarial local and loco-regional control rates were calculated by using the Kaplan-Meier method [19]. The Fisher's exact test, the unpaired ttest, and the logrank test were used to assess for significant differences between simple proportions, means, and survival curves respectively.
Results All the patients completed the planned irradiation schedule except one in the RT-CT group. All three treatment interruptions due to acute toxicity occurred in the RT-CT group (split duration 5, 17, and 35 days). The median overall treatment time was 41 days (range 36-50 days) for the RT group and 39 days (range 37-79) for the RT-CT group. The median tumor dose for both groups was similar (69.9 Gy, range 62.5-72.9). Morbidity
According to the RTOG grading system [20], all acute reactions were grade 2 or more. The majority were grade Chemotherapy 3 reactions, with only one patient in the RT group and two patients in the RT-CT group presenting with grade 4 In the initial patients chemotherapy was delivered sequentially prior to acute toxicity. The main acute toxicity parameters for starting RT. Apparently satisfactory tolerance led to a gradual shift toward the administration of an increasing proportion of the chemo- the two groups are displayed in Table 2. In the RT-CT therapy concomitantly with RT. Thus in 10 cases chemotherapy was group, grade 3 dysphagia was more frequent with conadministered only prior to, and in 25 concomitantly with RT, either comitant (64%) than with neoadjuvant (45%) chemoalone or with neoadjuvant and/or adjuvant chemotherapy. therapy administration. Except for two patients treated with weekly carboplatin, all patients According to the World Health Organization (WHO) received cisplatin (CDDP), associated with 5-fluorouracil (5-FU) in 28 grading system [21], 12 patients (36%) in the RT-CT patients, with epirubicin + bleomycin in four patients, and administered alone in one patient. Twenty-two (63%) patients received three group presented with grade 3-4 hematological complicycles, nine (26%) two cycles, and two (6%) one cycle. In patients cations. Grade 3 gastrointestinal complications were obreceiving at least part of their chemotherapy concomitantly with RT, served in four patients, and grade 3 skin reactions in one chemotherapy consisted of CDDP and 5-FU in 21 patients (84%). Fourteen patients received one cycle, and seven patients two cycles, patient. Three patients presented with a vascular thromadministered generally on the first and the fourth week of RT. CDDP bosis requiring anticoagulation, three with alopecia and (100 mg/m ) was given as a rapid intravenous infusion followed by one with hearing impairment.
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
NO Nl-3 AJCC stage III IV
RT group (52 patients)
683 Week
1
2
3
4
5
6
Wide fields (50.4 Gy/28 fr.)
XXXXX
XXXXX
XXXXX
XXXXX
XXXXX
XXX
X
X_X_X
x_xxx
XXX
Boost (19.5Gy/13 fr.)
X
Figure 1. Schematic representation of the radiotherapy protocol.
Clinical outcome
At last follow-up, 31 patients in the RT group and 17 in the RT-CT group were still alive, and one patient in each group was lost to follow-up (14 and 11 months). In patients having died, head and neck cancer was considered the cause of death in 14 of 20 patients in the RT group and 11 of 17 patients in the RT-CT group. The median follow-up for the surviving patients was 21 months (range 2-60) and 31 months (range 4-54) for the RT and RT-CT groups, respectively. Local and locoregional control rates were estimated for patients with a minimum follow-up of one year and without taking into account the contribution of salvage surgery. At three years actuarial local control was 70% in the two groups and actuarial loco-regional control was 57% and 66% for the RT and RT-CT groups, As expected from any accelerated RT program, the rate respectively (P = 0.66). The three-year actuarial overall of grade 3-4 acute reactions was high and was increased survival was 56% and 47% (P = 0.99), and the three-year by the adjunction of chemotherapy (Table 2). Indeed, disease-free survival was 53% and 60% for the RT and compared with the RT group, there was greater overall the RT-CT groups, respectively (P - 0.8). acute toxicity and significantly more grade 3 dysphagia in the RT-CT group, and patients receiving combined treatment more frequently required hospitalization and needed significantly more nutritional support. However, Discussion it is the authors' impression that acute toxicities were Unconventional radiation fractionation schedules and equally manageable in the two groups, particularly when the association of chemotherapy with RT represent the timely supportive care was provided. The most signifimain innovative approaches currently under study for cant therapeutic disadvantage of combined treatment the treatment of unfavorable head and neck cancers. was the occasional disruption of RT delivery. In this retrospective analysis, locoregional control, Progress in this area has been impeded by the problem of unacceptable acute toxicity, and various strategies disease-free survival, and overall survival were not sighave been developed to assure the feasibility of these nificantly different between the two groups. This appears aggressive treatment programs. In the case of acceler- to be in contradiction to the results of some randomized ated RT schedules, tolerance has been variously im- studies comparing concomitant chemoradiotherapy with proved by reducing the total dose (very accelerated RT alone, which demonstrate significantly better loco-
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
Three patients in the RT group and one in the RT-CT group died during the three months following radiotherapy of causes not clearly related to tumor progression. One patient, who refused supportive care, died of malnutrition; one malnourished patient died from Candida septicemia; one patient died from pneumonia as a consequence of severe laryngeal edema; and one patient died from a massive oropharyngeal hemorrhage in a setting of post-chemotherapy thrombopenia. Seventy-three patients were evaluable for long-term complications (patients with a minimum follow-up of three months and with available data). Most complications were RTOG grade 2 (52% and 42% in the RT and RT-CT groups, respectively). Grade 3-4 complications were observed in 5% and 12% in the RT and RT-CT groups, respectively (P = 0.4).
continuous course), interposing a treatment gap (accelerated split course), or reducing the volume submitted to accelerated fractionation (concomitant boost). On the other hand, for combinations of chemo- and radiotherapy, many investigators have preferred sequential or alternating schedules, in order to avoid the toxicity associated with the concomitant administration of the two modalities. Moreover, chemotherapy has often been limited to single agents, and RT administered using standard fractionation or using split course techniques. In contrast, the feasibility of concomitant chemotherapy and continuous accelerated RT has not been extensively investigated. There is increasing evidence that locoregional control can be improved through the use of various hyperfractionated and accelerated RT programs [1, 4, 6, 9, 22]. Considering the logistical convenience and the encouraging initial results of concomitant boost schedules [9], a modified concomitant boost program was developed, in which the 13 second daily fractions were given in a progressively accelerated manner starting on day 12 of the basic treatment. This schedule design was based on the notion, as suggested by both experimental and clinical data [23, 24], that cancer clonogen repopulation may become significant as early as two weeks after initiation of RT, and that the incremental dose required to compensate for tumor proliferation might increase progressively toward the end of treatment. At the same time, and with the aim of increasing the efficacy of this accelerated RT schedule, selected patients with very advanced disease were given chemotherapy. Initially chemotherapy was given sequentially before RT, but since this mode of administration had come under serious criticism [8, 11, 25], a decision was made to give at least part of the chemotherapy concomitantly with irradiation. The choice of 5-FU/CDDP was motivated by the reported activity of this combination in head and neck cancers [3, 12] and by the radiosensitizing properties attributed to CDDP [26, 27].
684
20.
References
21.
1. Horiot JC, Le Fur R, N'Guyen Tet al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: Final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992; 25: 231-41. 2. Sanchiz F, Milla A, Torner J et al. Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys 1990; 19: 1347-50. 3. Merlano M, Vitale V, Rosso R et al. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992; 327: 1115-21. 4. Wang CC, Blitzer PH, Suit H. Twice-a-day radiation therapy for cancer of the head and neck. Cancer 1985; 55: 2100-4. 5. Van den Bogaert W, Van der Schueren E, Horiot JC et al. Early results of the EORTC randomized clinical trial on multiple fractions per day (MFD) and misonidazole in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1986; 12: 587-91. 6. Horiot JC, Bontemps P, Begg AC et al. Hyperfractionated and accelerated radiotherapy in head and neck cancers: Facts from trials, impact on standard practice. Eur J Cancer 1995; 31A (Suppl 5): S69. 7. Hong WK, Bromer R. Current concepts: Chemotherapy in head and neck cancer. N Engl J Med 1983; 308: 75-9. 8. Vokes EE, Weichselbaum RR, Lippman SM, Ki Hong W. Head and neck cancer. N Engl J Med 1993; 328: 184-94. 9. Ang KK, Peters LJ, Weber RS et al. Concomitant boost radiotherapy schedules in the treatment of carcinoma of the oropharynx and nasopharynx. Int J Radiat Oncol Biol Phys 1990; 19: 1339^*5. 10. Wang CC. Carcinoma of the oropharynx. In Wang CC (eds): Radiation Therapy for Head and Neck Neoplasms. Chicago: Year Book Medical Publishers, 1990; 186-206. 11. Stell PM, Rawson NSB. Adjuvant chemotherapy in head and neck cancer. Br J Cancer 1990; 61: 779-87. 12. Taylor SG, Murthy AK, Caldarelli DD et al. Combined simulta-
22.
13.
14.
15.
16.
17.
18. 19.
23. 24.
25. 26. 27. 28. 29.
neous cisplatin/fluorouracil chemotherapy and split course radiation in head and neck cancer. J Clin Oncol 1989; 7: 846-56. Browman GP, Cripps C, Hodson DI et al. Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol 1994; 12: 2648-53. Gupta NK, Pointon RC, Wilkinson PM. A randomised clinical trial to contrastradiotherapywith radiotherapy and methotrexate given synchronously in head and neck cancer. Clin Radiol 1987; 38: 575-S1. Fu KK, Phillips TL, Silverberg IJ et al. Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: Update of a Northern California Oncology Group randomized trial. J Clin Oncol 1987; 5: 1410-8. Lo TCM, Wiley AL, Ansfield FJ et al. Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and orpharaynx: A randomized study. Am J Roentgenol RadiumTher Nucl Med 1976; 126: 229-35. Adelstein DJ, Saxton JP, Lavertu P et al. Concurrent radiation and chemotherapy versusradiotherapyalone in resectable stage III and IV squamous cell head and neck cancer. J Clin Oncol 1996; 15: 26 (Abstr). Knee R, Fields RS, Peters LJ. Concomitant boost radiotherapy for advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1985; 4: 1-7. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. Perez CA, Brady LW. Overview. In Perez CA, Brady LW (eds): Principales and Practice of Radiation Oncology. Philadelphia: Lippincott, 1992; 51-5. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treament. Cancer 1981; 47: 207-14. Saunders MI, Disch S, Grosch, EJ et al. Experience with CHART. Int J Radiat Oncol Biol Phys 1991; 21: 871-S. Withers HR, Taylor JMG, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27: 131^46. Kummermehr J, Schropp K, Neuner M. Repopulation in squamous cell carcinoma AT 478 during daily irradiation. Experimentelle Tumor-therapie, Annual Report 1985, Munich, GSF-Bericht 31/85,1986; 31-6. Jacobs C. Adjuvant and neoadjuvant treatment of head and neck cancers. Semin Oncol 1991; 18: 504-14. Overgaard J, Khan AR. Selective enhancement of radiation response in C3H mammary carcinoma by cisplatin. Cancer Treat Rep 1981; 65: 501-3. Douple EB. Radiosensitization of hypoxic tumor cells by cis- and trans-dichiorodiammine platinum (II). Int J Radiat Oncol Biol Phys 1979; 5: 1369-72. Munro AJ. An overview of randomised controlled trials of adjuvant chemotherapy in head and neck cancer. Br J Cancer 1995; 71: 83-91. El-Sayed S, Nelson N. Adjuvant and adjunctive chemotherapy in the management of squamous cell carcinoma of the head and neck region: A meta-analysis of prospective and randomized trials. J Clin Oncol 1996; 14: 838-47.
Received 31 January 1997; accepted 28 May 1997.
Correspondence to: A. S. Allal, MD Division of Radiation Oncology University Hospital 1211 Geneva 14 Switzerland
Downloaded from http://annonc.oxfordjournals.org/ at North Dakota State University on May 28, 2015
regional control [14—16], and suggest a statistically significant improvement in survival with combined treatment [28, 29]. However, as a result of patient selection, the composition of the two groups in the present study was not at all similar (Table 1). In particular, in the RTCT group there were fewer patients having had neck dissections and a higher percentage of T3-T4 tumors. It is thus impossible to draw conclusions from the current study regarding the potential benefits of the combined treatment. In the absence of randomized comparisons the choice of RT regimen for treating unfavorable head and neck cancers will be determined by convenience, toxicity profile, and the feasibility of administration simultaneously with effective antitumor agents. Although highly accelerated continuous regimens are likely to be incompatible with such combined therapy, our initial clinical results suggest that the concomitant boost program described in the present paper can be administered together with standard combination chemotherapy with acceptable toxicity. The locoregional control obtained in the present series of patients with stage III—IV disease is encouraging. A confirmation of these results in prospective studies appears justified.